virus (VSV), and use this information to design more effective, safer recombinant live virus vaccines against Yersinia pestis and pox viruses. Previous strategies for attenuating pathogenesis of recombinant VSV vaccine vectors have focused on reducing the ability of the virus to produce infectious progeny. This has the I The goal of this project is to identify the mechanisms that account for pathogenesls of vesicular stomatitis undesired effect of reducing the level of antigen expression and reducing the subsequent immune response. In contrast, we have developed a new strategy for attenuating viral pathogenesis by reducing the ability of the virus to suppress host innate immune responses without compromising the yield of infectious progeny or the level of antigen expression from infected cells.These vectors are designed to have greater efficacy by enhancing innate immune mechanisms and greater safety by modifying the determinants of viral pathogenesis. Aim 1 is to determine the pathogenesis and cytokine production by VSV vectors that activate innate immune mechanisms. These experiments involve analysis of virus dissemination and cytokine production in mice infected with recombinant M protein mutant viruses, which fail to suppress host innate immune responses, and recombinant viruses that express Salmonella flagellin as an activator of toll-like receptors responsible for induction of innate immune responses. Aim 2 is to test the hypothesis that activation of innate immune mechanisms by mutant viruses leads to more effective adaptive immune responses. The ability of recombinant mutant VSV vectors to elicit antibodies against a bacterial pathogen and to protect against bacterial challenge will be tested using vectors that express the F1 and V antigens of Y. pestis. The ability of these vectors to elicit cytotoxic T lymphocytes and protect against respiratory challenge with poxviruses will be tested using vectors that express surrogate antigens expressed by recombinant vaccinia viruses. These experiments address directly the dilemma faced in developing attenuated viruses as vaccines: a virus that is too attenuated for growth will not elicit a very effective immune response, while one that is not attenuated enough will be unsafe. In contrast, a virus that is attenuated by being unable to suppress the host response may be a more effective and safer vaccine.